Connexin 43 (Cx43) is a gap junction gene which has an essential role in heart development. This is indicated by the finding that Cx43 knockout mice die at birth from right ventricular outflow models suggests that the requirement for Cx43 gap functions in heart development likely involves two extracardiac cell populations, the neural crest and the epicardially derived (EPD) cells. The objectives of this project are two fold: to elucidate the cell signaling pathways involved in regulating gap junction communication and the migration of cardiac neural crest ells, and analysis of the role of Cx43 in the mobilization of EPD cells. From these studies, a new paradigm may emerge on the cellular mechanisms that modulate the homing of migratory cells in the developing embryo. As the Cx43 knockout mice show cardiac anomalies similar to that found in patients with anomalous coronary vessels, and subpulmonary atresia with intact ventricular septum, these studies may help establish a link between extracardiac cells and these two classes of as yet poorly understood congenital cardiac malformation. Moreover, as the coronary vessels play an important role in elaborating the cardiac conduction system, these studies also may help to elucidate the cellular mechanisms patterning the AV conduction system.